Desigualdades sociais no diagnóstico do câncer do colo do útero no Brasil: um estudo de base hospitalar / Social inequalities in the diagnosis of cervical cancer in Brazil: a hospital-based study

Resumo O estudo visa analisar a prevalência de estadiamento avançado ao diagnóstico do câncer do colo do útero e sua associação com indicadores individuais e contextuais socioeconômicos e de oferta de serviços de saúde no Brasil. Estudo transversal, realizado com casos de câncer do colo do útero em mulheres de 18 a 99 anos, no período de 2006 a 2015, extraídos do Integrador de Registros Hospitalares de Câncer. Variáveis contextuais foram coletadas no Atlas do Desenvolvimento Humano, no Cadastro Nacional de Estabelecimentos de Saúde e no Sistema de Informações Ambulatoriais. Usou-se o modelo de regressão de Poisson multinível com intercepto aleatório. A prevalência de diagnóstico em estádio avançado foi de 48,4%, apresentando associação com idades mais avançadas (RP 1,06; IC 1,01-1,10), raça/cor da pele preta, parda e indígena (RP 1,04; IC 1,01-1,07), menores níveis de escolaridade (RP 1,28; IC 1,16-1,40), ausência de parceiro conjugal (RP 1,10; IC 1,07-1,13), encaminhamento do tipo público ao serviço de saúde (RP 1,07; IC 1,03-1,11) e menor taxa de realização de exame citopatológico (RP 1,08; IC 1,01-1,14). Os resultados reforçam a necessidade de melhorias no programa nacional de prevenção do câncer do colo do útero em áreas com baixa cobertura da citologia oncótica.

Abstract The scope of this study is to analyze the prevalence of advanced stage diagnosis of cervical cancer and its association with individual and contextual socioeconomic and healthcare service indicators in Brazil. A cross-sectional study was conducted using cervical cancer cases in women aged 18 to 99 years, from 2006 to 2015, extracted from the Hospital Cancer Registry (HCR) Integrator. Contextual variables were collected from the Atlas of Human Development in Brazil; the National Registry of Health Institutions (NRHI); and the Outpatient Information System. Multilevel Poisson Regression with random intercept was used. The prevalence of advanced stage diagnosis was 48.4%, revealing an association with older age groups (PR 1.06; CI 1.01-1.10), black, brown, and indigenous race/skin color (PR 1.04; CI 1.01-1.07), lower levels of schooling (PR 1.28; CI 1.16-1.40), no marital partner (PR 1.10; CI 1.07-1.13), public referral to the health service (PR 1.07; CI 1.03-1.11), and lower rates of cytological examination (PR 1.08; CI 1.01-1.14). The results reinforce the need for improvements in the national cervical cancer prevention program in areas with low coverage of oncotic cytology.

Phytochemical profile and biological activities of Bromelia antiacantha extracts / Perfil fitoquímico e atividades biológicas de extratos de Bromelia antiacantha

Reports from popular medicine usually act as a basis for the development of new drugs from natural compounds with therapeutic actions for serious diseases and prevalence such as cancer. Bromelia antiacantha Bertol. is a species of the Bromeliaceae family, considered an unconventional food plant, found in the south and midwest regions of Brazil. Despite the high nutritional content and pharmacological potential of its fruits, few scientific studies report its biological actions. Thus, this study evaluates the phytochemical profile of aqueous and ethanol extracts obtained from B. antiacantha fruits, as well as their possible antioxidant, antitumor, and cytotoxic activities. The aqueous extract exhibited phenolic compounds and flavonoids, while ethanol extracts indicated the presence of flavonoids and coumarin in their composition, regardless of the region of collection. The ethanolic extract demonstrated a more promising antioxidant effect than the aqueous extract and also induced a significant inhibition in the viability of human cervical cancer cells of the SiHa strain. In addition, treatment with both extracts did not alter the viability of non-tumor cells of the immortalized human keratinocyte lineage (HaCaT). These results bring new data about extracts obtained from a native plant, edible and traditionally used in popular medicine, opening new perspectives for its possible therapeutic application.

Relatos da medicina popular costumam atuar como referencial para o desenvolvimento de novos fármacos a partir de moléculas naturais com ações terapêuticas para doenças de alta gravidade e prevalência como o câncer. Bromelia antiacantha Bertol. é uma espécie da família Bromeliaceae, considerada uma planta alimentícia não convencional (PANC), encontrada nas regiões sul e centro-oeste do Brasil. Apesar do alto teor nutritivo e potencial farmacológico de seus frutos, poucos estudos científicos relatam suas ações biológicas. Desta forma, este estudo avalia o perfil fitoquímico de extratos aquoso e etanólico obtidos de frutos de B. antiacantha, bem como a sua possível ação antioxidante, antitumoral e citotóxica. O extrato aquoso apresentou compostos fenólicos e flavonoides, enquanto os extratos etanólicos apontam a presença de flavonóides e cumarina em sua composição, independente da região de coleta. O extrato etanólico demonstrou efeito antioxidante mais promissor do que o extrato aquoso e também induziu uma inibição significativa na viabilidade de células humanas de câncer cervical da linhagem SiHa. Além disso, o tratamento com ambos extratos não alterou a viabilidade de células não tumorais da linhagem de queratinócitos humanos imortalizados (HaCaT). Estes dados trazem novas informações sobre extratos obtidos de uma espécie vegetal nativa, comestível e já utilizada tradicionalmente, mas abrindo novas perspectivas quanto a possíveis aplicações terapêuticas.

Phytochemical profile and biological activities of Bromelia antiacantha extracts

Abstract Reports from popular medicine usually act as a basis for the development of new drugs from natural compounds with therapeutic actions for serious diseases and prevalence such as cancer. Bromelia antiacantha Bertol. is a species of the Bromeliaceae family, considered an unconventional food plant, found in the south and midwest regions of Brazil. Despite the high nutritional content and pharmacological potential of its fruits, few scientific studies report its biological actions. Thus, this study evaluates the phytochemical profile of aqueous and ethanol extracts obtained from B. antiacantha fruits, as well as their possible antioxidant, antitumor, and cytotoxic activities. The aqueous extract exhibited phenolic compounds and flavonoids, while ethanol extracts indicated the presence of flavonoids and coumarin in their composition, regardless of the region of collection. The ethanolic extract demonstrated a more promising antioxidant effect than the aqueous extract and also induced a significant inhibition in the viability of human cervical cancer cells of the SiHa strain. In addition, treatment with both extracts did not alter the viability of non-tumor cells of the immortalized human keratinocyte lineage (HaCaT). These results bring new data about extracts obtained from a native plant, edible and traditionally used in popular medicine, opening new perspectives for its possible therapeutic application.

Resumo Relatos da medicina popular costumam atuar como referencial para o desenvolvimento de novos fármacos a partir de moléculas naturais com ações terapêuticas para doenças de alta gravidade e prevalência como o câncer. Bromelia antiacantha Bertol. é uma espécie da família Bromeliaceae, considerada uma planta alimentícia não convencional (PANC), encontrada nas regiões sul e centro-oeste do Brasil. Apesar do alto teor nutritivo e potencial farmacológico de seus frutos, poucos estudos científicos relatam suas ações biológicas. Desta forma, este estudo avalia o perfil fitoquímico de extratos aquoso e etanólico obtidos de frutos de B. antiacantha, bem como a sua possível ação antioxidante, antitumoral e citotóxica. O extrato aquoso apresentou compostos fenólicos e flavonoides, enquanto os extratos etanólicos apontam a presença de flavonóides e cumarina em sua composição, independente da região de coleta. O extrato etanólico demonstrou efeito antioxidante mais promissor do que o extrato aquoso e também induziu uma inibição significativa na viabilidade de células humanas de câncer cervical da linhagem SiHa. Além disso, o tratamento com ambos extratos não alterou a viabilidade de células não tumorais da linhagem de queratinócitos humanos imortalizados (HaCaT). Estes dados trazem novas informações sobre extratos obtidos de uma espécie vegetal nativa, comestível e já utilizada tradicionalmente, mas abrindo novas perspectivas quanto a possíveis aplicações terapêuticas.

Prevalence of high-risk human papillomavirus genotypes among apparently healthy women with normal and abnormal cervical cytology in Kaduna State, Nigeria

Background: About 99.7% of cervical dysplasia and cancer cases are caused by persistent genital high-risk human papillomavirus (hrHPV) infection. Most HPV infections are subclinical and self-limiting but may persists in about 5 to 10% of infected women, resulting in pre-cancerous lesions that can progress to invasive cancer years later. This study is aimed at detecting hrHPV among apparently healthy women of reproductive age in Kaduna State, thus providing more information for effective control of HPV and cervical cancer in Nigeria. Methodology: Cervical smears were taken from 515 randomly selected apparently healthy women across selected secondary and tertiary facilities from 3 Local Government Areas (LGAs) in each Senatorial Zone of Kaduna State, Nigeria. Liquid-based cytology (LBC) technique was used to collect cervical smears and prepare smears for cytology study, while the remaining samples were stored at -80oC for molecular studies. HPV DNA were extracted from the samples and amplified by convectional PCR using specific hrHPV (HPV 16,18,31 and 45) primer sets and a broad spectrum MY09/11 and GP5+/6+ primers for a wider range of HPV genotypes. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 23.0 and relationship between prevalence of hrHPV and socio-demographic factors such as age and marital status were determined using Chisquare or Fisher Exact test with p<0.05 considered statistically significant. Results: The prevalence of total HPV and hrHPV infections in the study population was 11.8% (61/515) and 9.3% (48/515) respectively. A total of 100 HPV genotypes were detected by PCR in the 61 positive smears, with 66 hrHPV types from 48 women, and 34 other HPV types from 13 women. The frequency of hrHPV genotypes detected was HPV 31 (5.8%, n=30), HPV 45 (4.1%, n=21), HPV 16 (1.7%, n=9), and HPV 18 (1.2%, n=6), with other HPV genotypes (6.6%, n=34). The frequency of cervical dysplasia was 6.4% (33/515), which was significantly associated with all HPV genotypes except HPV 16. Single HPV infection was seen in 31 (51.8%) women while multiple infections were seen in 30 (49.2%), with double infection in 21 (34.4%) and triple infections in 9 (14.7%). Conclusion: The prevalence of hrHPV infection was high among women in Kaduna State, Nigeria. DNA-based screening for hrHPV genotypes and production of new vaccine that will protect against the predominant hrHPV genotypes are thus recommended for the prevention of cervical cancer in Nigeria, Africa and beyond.

Expert Consensus on Standardized Construction of Integrated Outpatient Clinic for Cervical Cancer Prevention and Control in Hubei Provincial Grassroots Maternal and Child Health Hospitals / 肿瘤防治研究

Cervical cancer is a malignant tumor that can be effectively controlled and eventually eliminated through etiological prevention, pathogenic prevention, and clinical prevention. In China, some problems exist in comprehensive prevention and control system for cervical cancer, such as uneven development, insufficient capacity building, and scattered institutions. In 2022, the Hubei Provincial Government launched a province-wide project to provide free cervical cancer screening for 12.67 million women aged 35-64 from 2022 to 2024. It is a historic opportunity and of great significance to fully utilize the scale and team advantages of this full-coverage cervical cancer screening, build integrated outpatient clinic for cervical cancer prevention in grassroots maternal and child health hospitals, and implement standardized construction and management. The expert group of the Cervical Disease Prevention and Control Professional Committee of Hubei Maternal and Child Health Association formulated this consensus based on the latest progress and the actual situation in Hubei. The consensus elucidated the general requirements, HPV vaccination outpatient construction standards and workflow, cervical cancer screening outpatient construction standards and workflow, colposcopy outpatient construction standards and workflow, precancerous lesion treatment outpatient construction standards and workflow, the follow-up after treatment of precancerous lesions, public education, etc. This consensus is suitable for guiding the standardized construction and management of integrated outpatient clinics for cervical cancer prevention and control in grassroots (county, district) maternal and child health hospitals in Hubei province.

Survival Status of Patients with Cervical Cancer Registered in Nantong / 肿瘤防治研究

Objective To analyze the survival status of inpatients with cervical cancer registered in Nantong admitted in Nantong Cancer Hospital from 2002 to 2017. Methods Inpatients with cervical cancer in Nantong Cancer Hospital were followed up from 2017 until December 31, 2020 using active and passive methods to determine their survival outcome. The rate of follow-up loss was statistically analyzed by Chi-square test, the observed survival rate for each year was calculated using the life table, the survival curve was drawn with R language, and the survival rates of patients in different age groups and from different regions were compared with log-rank test (Mantel-Cox). Results A total of 5645 cervical cancer cases were registered. Among them, the survival outcome was recorded for 5512 cases. The success rate of follow-up was 97.64%, and the loss of follow-up rate was 2.36%. The average age of onset was 56.67±12.78 years. The median survival time was 6.54 years, and the 1-, 3-, 5-, and 10-year observed survival rates were 91.50%, 76.95%, 60.99%, and 28.51%, respectively. Among the age groups, significant differences in survival rate were observed between the 15- and 60-year-old groups (χ2=7.469, P=0.006) and between the 15- and 80-year-old groups (χ2=36.317, P < 0.001). No significant difference in survival rate was found between patients from Haimen and Qidong (χ2=2.779, P=0.095) and between patients from Qidong and Tongzhou (χ2=0.515, P=0.473). Significant difference in survival rate was observed among other regions (P < 0.05). Conclusion In this study group, the survival rates of hospital-based patients with cervical cancer significantly differ among the age groups and regions of origin and significantly decreased with age. The high follow-up rate fully reflects the comprehensive effect of the treatment in Nantong Cancer Hospital for registered patients with cervical cancer in Nantong.

Asperuloside Promotes Apoptosis of Cervical Cancer Cells through Endoplasmic Reticulum Stress-Mitochondrial Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of asperuloside on cervical cancer based on endoplasmic reticulum (ER) stress and mitochondrial pathway.@*METHODS@#Different doses (12.5-800 µg/mL) of asperuloside were used to treat cervical cancer cell lines Hela and CaSki to calculate the half maximal inhibitory concentration (IC50) of asperuloside. The cell proliferation was analyzed by clone formation assay. Cell apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were determined by flow cytometry. The protein expressions of cleaved-caspase-3, Bcl-2, Bax, Cyt-c, cleaved-caspase-4 and glucose-regulated protein 78 (GRP78) were analyzed by Western blot. And the inhibitor of ER stress, 4-phenyl butyric acid (4-PBA) was used to treat cervical cancer cells to further verify the role of ER stress in the apoptosis of cervical cancer cells induced by asperuloside.@*RESULTS@#Asperuloside of 325, 650, and 1300 µg/mL significantly inhibited the proliferation and promoted apoptosis of Hela and CaSki cells (P<0.01). All doses of asperuloside significantly increased intracellular ROS levels, reduced mitochondrial membrane potential, significantly reduced Bcl-2 protein expression level, and increased Bax, Cyt-c, GRP78 and cleaved-caspase-4 expressions (P<0.01). In addition, 10 mmol/L 4-PBA treatment significantly promoted cell proliferation and reduced apoptosis (P<0.05), and 650 µg/mL asperuloside could reverse 4-PBA-induced increased cell proliferation, decreased apoptosis and cleaved-caspase-3, -4 and GRP78 protein expressions (P<0.05).@*CONCLUSION@#Our study revealed the role of asperuloside in cervical cancer, suggesting that asperuloside promotes apoptosis of cervical cancer cells through ER stress-mitochondrial pathway.

Expression and Clinical Significance of KIF11,β-catenin and GSK-3β in Cervical Cancer / 医学研究杂志

Objective To investigate the expression of kinesin family member 11(KIF11),β-catenin and glycogen synthase ki-nase-3β(GSK-3β)in cervical cancer and its clinical significance.Methods The expression of KIF11,β-catenin and GSK-3β in 102 cases of cervical cancer,52 cases of high-grade squamous intraepithelial lesion(HSIL)and 46 cases of low-grade squamous intra-epithelial lesion(LSIL)and 40 cases of chronic cervicitis were detected by immunohistochemistry,to analyze the relationship between the expression of the three indicators and the clinicopathological characteristics of cervical cancer patients,and to analyze the correlation be-tween the three indicators.COX proportional hazards model was used to analyze the prognostic factors of cervical cancer patients.Results With the progression of cervical lesions,the positive rates of KIF1 1 and β-catenin increased gradually,while the positive rates of GSK-3β decreased gradually(P＜0.05).The positive expressions of KIF11,β-catenin and GSK-3β in cervical cancer tissues were significantly different in International Federation of Gynecology and Obstetrics(FIGO)stage,differentiation degree and lymph node metastasis(P＜0.05),but there was no significant difference among different ages and pathological types(P＞0.05).The expression level of KIF11 was positively correlated with β-catenin(r=0.461,P＜0.05),and the expression level of β-catenin was negatively correlated with GSK-3β(r=-0.692,P＜0.05).The expression level of KIF11 was negatively correlated with GSK-3β(r=-0.336,P＜0.05).The average survival time of patients with positive expression of KIF11 and β-catenin was shorter than that of pa-tients with negative expression,and the average survival time of patients with positive expression of GSK-3 β was longer than that of pa-tients with negative expression of GSK-3β.COX regression analysis showed that FIGO stage,lymph node metastasis,KIF11 and β-catenin were independent risk factors for the prognosis of cervical cancer patients,and GSK-3β was an independent protective factor.Conclusion KIF11,β-catenin and GSK-3β are abnormally expressed in the tissues of cervical cancer patients.KIF11 may be in-volved in the regulation of Wnt/β-catenin pathway in the development of cervical cancer.The combined detection of KIF11 may provide a new reference for the diagnosis and prognosis of cervical cancer.

hsa_circ_0011946 regulates the proliferation,migration and invasion of cervical cancer cells via targeting miR-767-3p / 局解手术学杂志

Objective To investigate the role of hsa_circ_0011946 targeting miR-767-3p in the progression of cervical cancer.Methods The expression levels of hsa_circ_0011946 and miR-767-3p in cervical cancer tissues,adjacent tissues,immortalized human cervical epithelial cells(H8)and cervical cancer cells(SiHa,HeLa,and Cashi)were determined by RT-qPCR.SiHa cells were transfected with si-NC,si-hsa_circ_0011946,miR-NC,miR-767-3p,pcDNA,pcDNA-hsa_circ_0011946,anti-miR-NC+si-hsa_circ_0011946,anti-miR-767-3p+ si-hsa_circ_0011946,respectively,as the si-NC group,the si-hsa_circ_0011946 group,the miR-NC group,the miR-767-3p group,the pcDNA group,the pcDNA-hsa_circ_0011946 group,the anti-miR-NC+si-hsa_circ_0011946 group,and the anti-miR-767-3p+si-hsa_circ_0011946 group,and the untransfected cells were used as the NC group.The expression of hsa_circ_0011946 and miR-767-3p of SiHa cells in each group was detected by RT-qPCR,the cell viability was detected by CCK-8,the number of cell clone was detected by plate clone formation assay,the cell migration and invasion numbers were detected by Transwell assay,and the protein expression of MMP-2 and MMP-9 was detected by Western blot.The binding site of miR-767-3p to hsa_circ_0011946 was predicted by circular RNA interactome,and the targeted relationship between hsa_circ_0011946 and miR-767-3p was analyzed by dual luciferase reporter assay.Results Compared with the adjacent tissues,the expression level of hsa_circ_0011946 in the cervical cancer tissues was significantly increased(P<0.05),while the expression level of miR-767-3p was significantly decreased(P<0.05).Compared with H8 cells,the expression levels of hsa_circ_0011946 in SiHa,HeLa and Caski cells were significantly increased(P<0.05),while the expression levels of miR-767-3p were signifi-cantly decreased(P<0.05).Compared with the NC group,the expression level of hsa_circ_0011946,absorbance(A)value,number of clone,number of migration,number of invasion and the protein expression levels of MMP-2 and MMP-9 were significantly decreased in SiHa cells in the miR-767-3p group(P<0.05).Compared with the miR-NC group,the expression level of miR-767-3p in SiHa cells in the miR-767-3p group was significantly increased(P<0.05),and the cell A value,number of clone,number of migration,number of invasion and the protein expression levels of MMP-2 and MMP-9 were significantly decreased(P<0.05).Compared with the pcDNA group,the expression level of miR-767-3p in SiHa cells in the pcDNA-hsa_circ_0011946 group was significantly decreased(P<0.05),and the expression level of hsa_circ_0011946 was significantly increased(P<0.05).The relative luciferase activity of SiHa cells co-transfected with miR-767-3p mimics and WT-hsa_circ_0011946 was lower than that of co-transfected with miR-NC and WT-hsa_circ_0011946(P<0.05).hsa_circ_0011946 bound to miR-767-3p directly and specifically.Compared with the anti-miR-NC+si-hsa_circ_0011946 group,the expression level of miR-767-3p in SiHa cells in the anti-miR-767-3p+si-hsa_circ_0011946 group was significantly decreased(P<0.05),and the cell A value,number of clone,number of migration,number of invasion and protein expression levels of MMP-2 and MMP-9 were significantly increased(P<0.05).Conclusion Interfering hsa_circ_0011946 can inhibit the proliferation,migration and invasion of cervical cancer cells through targeted up-regulation of miR-767-3p.

Curative effect and prognosis of Zheng′s 4C suspension transumbilical laparoendoscopic single-site surgery for cervical cancer / 局解手术学杂志

Objective To investigate the effect of Zheng's 4C suspension transumbilical laparoendoscopic single-site surgery(TU-LSSS)in the treatment of cervical cancer,and analyze its prognosis.Methods A total of 92 patients with cervical cancer admitted to our hospital were selected and randomly divided into the control group(traditional laparoscopic surgery)and the observation group(Zheng's 4C suspension TU-LSSS),with 46 cases in each group.The perioperative related indicators of patients between the two groups were compared.The patients were followed up for 3 years,the progression-free survival(PFS)and overall survival(OS)were recorded,and the influencing factors of prognosis were analyzed.Results Compared with the control group,patients in the observation group had longer surgical time(P<0.05),less intraoperative bleeding(P<0.05),shorter recovery time for postoperative bowel sounds and hospital stay(P<0.05),higher postoperative 3-year PFS rate and 3-year OS rate(P<0.05).During 3-year follow-up,there were 11 cases of disease progression or death.The univariate analysis results showed that there were statistically significant differences in tumor diameter,clinical stage,lymph node metastasis,vascular infiltration,and treatment methods of patients between the good prognosis group and the poor prognosis group(P<0.05).The binary Logistic regression results showed that tumor diameter(≥4 cm),clinical stage(≥stage ⅠB2),lymph node metastasis,and vascular infiltration were the risk factors for the prognosis of patietns with cervical cancer(P<0.05),while Zheng's 4C suspension TU-LSSS was the protective factors(P<0.05).Conclusion Zheng's 4C suspension TU-LSSS can effectively promote the recovery of patients with cervical cancer,and improve 3-year PFS rate and 3-year OS rate.The prognosis is related to many factors,and targeted treatment should be performed according to different risk factors.

Magnolol and 5-fluorouracil synergy inhibition of metastasis of cervical cancer cells by targeting PI3K/AKT/mTOR and EMT pathways / 中草药·英文版

OBJECTIVE@#This study is designed to investigate the mode of action of the synergistic effect of 5-fluorouracil (5-FU) and magnolol against cervical cancer.@*METHODS@#Network pharmacological approach was applied to predict the molecular mechanism of 5-FU combined with magnolol against cervical cancer. CCK-8 assay, colony formation assay, immunofluorescence staining, adhesion assay, wound healing mobility assay, cell migration and invasion assay and Western blot analysis were conducted to validate the results of in silico study.@*RESULTS@#Phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was identified as the key pathway in silico study. The experimental results showed that 5-FU combined with magnolol strongly inhibited cervical cancer cell proliferation, induced the morphological change of HeLa cells by down-regulating the expression of α-actinin, tensin-2 and vinculin. Moreover, magnolol enhanced inhibitory effect of 5-FU on the cell adhesion, migration and invasion. The phosphorylation of AKT and PI3K and the expression of mTOR were strongly inhibited by the combination of 5-FU and magnolol. Moreover, the expression of E-cadherin and β-catenin was upregulated and the expression of Snail, Slug and vimentin was down-regulated by the 5-FU together with magnolol.@*CONCLUSION@#Taken together, this study suggests that 5-FU combined with magnolol exerts a synergistic anti-cervical cancer effect by regulating the PI3K/AKT/mTOR and epithelial-mesenchymal transition (EMT) signaling pathways.

Effects of ligustilide on chemotherapy resistance of cervical cancer cells / 中国药房

OBJECTIVE To investigate the effects of ligustilide on chemotherapy resistance of cervical cancer cells based on Hippo-Yes-associated protein （YAP） signaling pathway. METHODS Human cervical cancer cisplatin-resistant cells HeLa/DDP were divided into control group， cisplatin group （10 μmol/L cisplatin）， cisplatin+ligustilide low-， medium- and high-concentration groups （10 μmol/L cisplatin+25， 50， 100 μmol/L ligustilide）. The proliferation， apoptosis， migration and invasion of HeLa/DDP cells were all detected in each group. The mRNA expressions of YAP and transcriptional coactivator with PDZ binding motif （TAZ） as well as the protein expressions of YAP， TAZ， matrix metalloproteinase 2 （MMP2）， Ki67， cleaved-caspase-3 and caspase-3 were determined in HeLa/DDP cells. RESULTS Compared with control group， the inhibitory rate， apoptotic rate and cleaved- caspase-3/caspase-3 of cisplatin group were increased significantly； scratch healing rate， the number of invasive cells， the mRNA expressions of YAP and TAZ， and the protein expressions of YAP， TAZ， MMP2 and Ki67 were decreased significantly in cisplatin group （P＜0.05）. Compared with cisplatin group， the inhibitory rate of cell proliferation， apoptotic rate and cleaved-caspase-3/ caspase-3 were further increased in cisplatin+ligustilide low-， medium- and high-concentration groups， while scratch healing rate， the number of invasive cells， the mRNA expressions of YAP and TAZ， and the protein expressions of YAP， TAZ， MMP2 and Ki67 were further decreased， in a dose-dependent manner （P＜0.05）. CONCLUSIONS Ligustilide can increase the sensitivity of drug-resistant cervical cancer cells to cisplatin by inhibiting Hippo-YAP signaling pathway.

Research status and vaccination policy of human papillomavirus vaccine / 上海预防医学

Cervical cancer is a common gynecological malignant tumor. Vaccination with human papilloma virus （HPV） vaccine is of great significance to prevent condyloma acuminatum， HPV infection， and cervical cancer. This paper reviews the epidemic situation and risk factors of cervical cancer， the prevention strategies of cervical cancer， HPV types， HPV vaccine types and mechanisms of action， the safety and effectiveness of vaccines， men’s HPV vaccination， vaccination policies in various countries and so on， and further puts forward suggestions on HPV vaccination policies in China.

Predictive value of a new radiotherapy plan evaluation tool for bladder toxicity in cervical cancer / 中国辐射卫生

Objective To evaluate the predictive value of a dose-surface histogram (DSH) for radiation cystitis (RC) in patients with cervical cancer. Methods We retrospectively included 190 patients with cervical cancer who underwent image-guided radiotherapy (IGRT) from the HIS system of The First Affiliated Hospital of Hebei North University from May 2013 to May 2023. The patients were divided into test group (n = 100) and control group (n = 90). The dose distribution in the bladder was evaluated by using a DSH for the test group and using a dose-volume histogram (DVH) for the control group. Receiver operating characteristic curves were used to evaluate the predictive value of DSH for RC in comparison with DVH. Results There were no significant differences in baseline data and RC incidence between the two groups (all P＞0.05). All evaluation indicators were significantly different between DSH and DVH (all P＜0.05). The predictive value of S45 and V45 for the incidence of grade-I, -II, and -III RC was low (all P＜0.05). The predictive value of S50 and V50 for the incidence of grade-I, -II, and -III RC was moderate (all P＜0.05). S55−S57 and V55−V57 showed high value for predicting the incidence of grade-I, -II, and -III RC (all P＜0.05). Conclusion DSH shows basically the same predictive value for the incidence of RC caused by IGRT in cervical cancer as DVH, which is expected to become a new tool for evaluating radiotherapy plans.

Mechanism of malignant behavior in cervical cancer cells based on NOD2-mediated AMPK/mTOR signaling pathway / 安徽医科大学学报

Objective To explore the mechanism of malignant behavior of cervical cancer(CC)cells based on AMP-activated protein kinase(AMPK)/rapamycin target protein(mTOR)signaling pathway mediated by nucleo-tide-binding oligomerization domain receptor 2(NOD2).Methods Bioinformatics analysis was performed to deter-mine the expression of NOD2 in CC tissue.Plasmids targeting NOD2(shNOD2)and shRNAs negative control(shNC),NOD2 overexpression(NOD2)and vectors(Vec)were transfected into CC cells.The effect of NOD2 on the growth of CC cells was determined by cell counting kit-8 assay,colony formation and Transwell cell invasion as-say.Transcriptome analysis was performed by high throughput RNA sequencing(RNA-Seq).Western blot was used to detect the expression of NOD2,AMPK/mTOR signaling pathway and autophagy protein in the cell line.24 female BALB/c nude mice were randomly divided into four groups,with 6 mice in each group:vector group(Vec group),NOD2 overexpression group(NOD2 group),shNC group and shNOD2 group.The distant metastasis mod-el was established in mice,and the fluorescence intensity of lung metastasis was monitored and the number of lung metastasis nodules was counted.Results On-line database analysis showed that the expression of NOD2 in CC tis-sues was significantly higher than that in normal tissues,and there were significant differences in the mRNA expres-sion of NOD2 in different stages of CC(P＜0.05).In addition,the high expression of NOD2 was associated with poor overall survival and disease-free survival(P＜0.05).NOD2 overexpression promoted the proliferation,colony formation,migration and invasion of CC cells,while NOD2 knock-down was the opposite.Consistent with the re-sults in vitro,the lung colonization and lung metastasis of CC cells in NOD2 group were significantly higher than those in Vec group(P＜0.05),while those in shNOD2 group were significantly lower than those in shNC group(P＜0.05).RNA-Seq results showed that the expression of NOD2 was significantly related to AMPK signal activa-tion,mTOR signal inhibition,autophagy regulation pathway activation and autophagy formation.Compared with shNC group,the expression of phosphorylated AMPK and LC3 protein decreased significantly in shNOD2 group(P＜0.05),and the expression levels of phosphorylated mTOR and p62 protein increased significantly(P＜0.05).Compared with Vec group,the expression levels of LC3 and AMPK protein in NOD2 group increased significantly(P＜0.05),and the expression levels of phosphorylated mTOR and p62 protein decreased significantly(P＜0.05).Compared with shNC group,the point accumulation of GFP-mRFP-LC3 in shNOD2 group decreased signifi-cantly(P＜0.05).Compared with Vec group,the point accumulation of GFP-mRFP-LC3 increased significantly(P＜0.05).Conclusion NOD2 may promote the proliferation,migration and invasion of CC through AMPK/mTOR signal,and its mechanism partly involves autophagy activation.

Combined detection of PAX1 methylation and p16/Ki-67 dual staining improves diagnostic performance for atypical squamous cells in cervical cancer / 陆军军医大学学报

Objective To compare paired boxed gene 1(PAX1)methylation and p16/Ki-67 double staining alone and in combination in thinprep cytologic test(TCT)for distinguishing atypical squamous cells of undetermined significance(ASC-US)and low-grade squamous intraepithelial lesion(LSIL)population.Methods A total of 247 patients with TCT results of ASC-US and LSIL admitted in our hospital from January 2021 to December 2022 were enrolled in this study.Detection efficacy of PAX1 methylation and p16/Ki-67 double staining alone and in combination was evaluated with colposcopic pathologic results as the gold standard and the sensitivity,specificity,accuracy and area under the curve(AUC)as evaluation indexes.Results The positive rates of PAX1 methylation and p16/Ki-67 double staining were increased with the severity of pathological findings.Combined detection of PAX1 methylation and p16/Ki-67 assay had a sensitivity of 91.25％,specificity of 97.72％and accuracy of 95.51％in the women with TCT of ASC-US,and these values were statistically better than those of PAX1 methylation and p16/Ki-67 double staining alone(P＜0.01).Conclusion The combination of PAX1 methylation and p16/Ki-67 double-staining assay can further improve the diagnostic efficacy in patients with ASC-US on TCT results.

HPV16 E6 mediates oncogenic transformation of cervical epithelial cells by downregulating DHRS2 expression / 陆军军医大学学报

Objective To explore the effects of HPV16 E6 on genes and signaling pathways in cervical epithelial cells and to screen genes associated with oncogenic transformation.Methods HUCEC models infected with HPV16 E6 were constructed,and transcriptome sequencing was performed to screen for differentially expressed genes(DEGs),which were subjected to Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment to analyze the differential signaling pathways.RT-qPCR was used to validate major differentially down-regulated expressed genes.After predicting the major differentially expressed proteins by molecular docking analysis,the expression of major differential genes in HUCEC cell model was verified by RT-qPCR and Western blotting.In addition,RT-qPCR and Western blotting were used to further verify the expression of major differential genes in cervical cancer cell lines,SiHa and CaSki.Results A total of 55 genes with more than two-fold differential expression were screened.The results centering on down-regulated genes showed that the negatively regulated differential gene was mainly enriched in redox processes;KEGG enrichment analysis revealed that it was mainly associated with carbohydrate metabolism and cancer.RT-qPCR results showed that the down-regulated differential expression trends of the selected 10 genes were basically consistent with the sequencing results.Molecular docking analysis predicted an interaction between DHRS2 and HPV16 E6,and RT-qPCR and Western blotting confirmed that HPV16 E6 down-regulated DHRS2 mRNA(P＜0.01)and protein(P＜0.05)and ETV5 protein expression(P＜0.01).In SiHa and CaSki cells,compared with the control group,the mRNA and protein expression of DHRS2 was downregulated and positively correlated with the trend of P53 protein expression(P＜0.05).Conclusion HPV16 E6 can mediate oncogenic transformation of cervical cells and promote cervical carcinogenesis through downregulating DHRS2 expression.

Expression of serum lncRNA CCDC18-AS1 and miR-501 in patients with HPV-infected cervical cancer and its correlation with prognosis / 国际检验医学杂志

Objective To explore the expression of serum long noncoding RNA(lncRNA)CCDC18-AS1 and microRNA-501(miR-501)in patients with human papillomavirus(HPV)-infected cervical cancer,and its correlation with prognosis.Methods A total of 78 patients with HPV-infected cervical cancer who underwent treatment in the hospital from May 2019 to May 2020 were enrolled as study group,meantime,80 patients with simple HPV infection and 81 patients with simple non-HPV infected cervical cancer were set as control group 1 and control group 2.Serum lncRNA CCDC18-AS1 and miR-501 expression levels were detected by re-al-time quantitative PCR.Then the clinical features,postoperative overall survival and progression-free surviv-al were analyzed in the study group.Results The relative expression levels of serum lncRNA CCDC18-AS1 and miR-501 in the study group were higher than those in control group 1 and control group 2(P<0.05),and the relative expression levels of serum lncRNA CCDC18-AS1 and miR-501 in control group 2 were higher than those in control group 1(P<0.05).Pearson correlation analysis showed that serum lncRNA CCDC18-AS1 and miR-501 were positively correlated in the study group(r=0.421,P<0.001).Serum lncRNA CCDC18-AS1 and miR-501 in study group were not related to age,but were related to clinical stage,differentiation de-gree,lymph node metastasis,and squamous epithelial cell antigen(P<0.05).Kaplan Meier analysis showed that the postoperative overall survival and progression-free survival of high lncRNA CCDC18-AS1 and miR-501 expression groups were shorter than those of low expression groups(P<0.05).Conclusion HPV-infec-ted cervical cancer patients have up-regulated expression of serum lncRNA CCDC18-AS1 and miR-501,and the abnormal changes are closely related to patients'clinical characteristics and postoperative survival,so the two indicators could be used as auxiliary indicators for the disease assessment and prognosis evaluation.

The value of HPV DNA and HPV E6/E7 mRNA detection in screening for cervical lesions / 国际检验医学杂志

Objective To investigate the value of human papillomavirus(HPV)DNA and HPV E6/E7 mRNA detection in screening for cervical lesions.Methods A total of 619 patients who were screened for cer-vical lesions in West China Second University Hospital from September 2021 to August 2022 were selected as the study objects.The value of HPV DNA and HPV E6/E7 mRNA detection in cervical lesion screening was evaluated based on their pathological results.Results The positive rate of HPV DNA detection was 64.78％(401/619)and that of HPV E6/E7 mRNA detection was 60.74％(376/619)in 619 patients.Cervical lesion screening was mainly conducted in sexually active people aged 30-＜40 years and 40-＜50 years.The posi-tive rates of HPV DNA and HPV E6/E7 mRNA increased with the increase of cervical lesion grade.The sen-sitivity,positive predictive value and negative predictive value of the two methods were higher than those of HPV DNA or HPV E6/E7 mRNA detection.Conclusion The combined detection of the two methods can be used for screening cervical lesions at various pathological stages,which can provide greater guidance value in clinical diagnosis and treatment.

Effect of sorafenib induced apoptosis and autophagy on drug resistance in HeLa cells / 基础医学与临床

Objective To explore the effect of sorafenib on HeLa cell proliferation by inducing cell apoptosis and autophagy and its impact on drug resistance.Methods The drug-resistant cell strains were constructed through in-termittent induction method,with concentrations of 0,2.5,5.0,7.5,10.0,15.0,20.0 μmol/L.HeLa cells were incubated with increasing concentrations of sorafenib with each concentration for 1 week.The drug-resistant cell strains with stable passages were collected.MTT assay was used to detect the effect of sorafenib on cell prolifer-ation.Cell cycle distribution was analyzed by flow cytometry.The change in the expression of drug-resistant and ap-optotic genes in the parents and drug-resistant cell strains under different drug concentrations was examined by semi-quantitative PCR.The changes of apoptotic related marker proteins LC3-Ⅰ and LC3-Ⅱ were detected by Westernblot.Results Stable drug-resistant strains were successfully obtained;Drug-treated cells were more blocked in the G1 phase.In drug-resistant cells,the expression of apoptosis suppressor gene Bcl-2 was significantly decreased and the apoptotic gene Bax as well as the drug-resistant genes were all significantly increased(P＜0.05).The LC3-Ⅱ/LC3-Ⅰ ratio of drug-resistant cells was significantly higher than that of parent cells(P＜0.05).Conclusions Sorafenib may block the cell cycle,suppress malignant cell proliferation and promote autophage.On one hand,autophagy participates in the development of cell drug resistance and promotes cell survival.On the other hand,drug-induced autophagy may activate some of apoptotic signaling pathway in drug-resistant cells and promote the reversal of cell drug resistance.